Differential expression of MUC4, GPR110 and IL2RA defines two groups of CRLF2-rearranged acute lymphoblastic leukemia patients with distinct secondary lesions. (1st November 2017)

• Record Type: Journal Article
• Authors: Sadras, Teresa; Heatley, Susan L.; Kok, Chung H.; Dang, Phuong; Galbraith, Kate M.; McClure, Barbara J.; Muskovic, Walter; Venn, Nicola C.; Moore, Sarah; Osborn, Michael; Revesz, Tamas; Moore, Andrew S.; Hughes, Timothy P.; Yeung, David; Sutton, Rosemary; White, Deborah L.
• Is Part Of: Cancer letters. Volume 408(2017)
• Page Start: 92
• Page End: 101
• Publication Date: 2017-11-01
• Subjects: Lymphoblastic leukemia -- JAK2 -- Genomics; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2017.08.034
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: CRLF2- rearrangements ( CRLF2 -r) occur frequently in Ph-like B-ALL, a high-risk ALL sub-type characterized by a signaling profile similar to Ph + ALL, however accumulating evidence indicates genetic heterogeneity within CRLF2 -r ALL. We performed thorough genomic characterization of 35 CRLF2 -r cases ( P2RY8-CRLF2 n = 18; IGH-CRLF2 n = 17). Activating JAK2 mutations were present in 34% of patients, and a CRLF2 -F232C mutation was identified in an additional 17%. IKZF1 deletions were detected in 63% of cases. The majority of patients (26/35) classified as Ph-like, and these were characterized by significantly higher levels of MUC4, GPR110 and IL2RA / CD25 . In addition, Ph-like CRLF2 -r samples were significantly enriched for IKZF1 deletions, JAK2/CRLF2 mutations and increased expression of JAK/STAT target genes ( CISH, SOCS1 ), suggesting that mutation-driven CRLF2/JAK2 activation is more frequent in this sub-group. Less is known about the genomics of CRLF2 -r cases lacking JAK2 -pathway mutations, but KRAS/NRAS mutations were identified in 4/9 non-Ph-like samples. This work highlights the heterogeneity of secondary lesions which may arise and influence intracellular-pathway activation in CRLF2 -r patients, and importantly presents distinct therapeutic targets within a group of patients harboring identical primary translocations, for whom efficient directed therapies are currently lacking. Highlights: CRLF2 -r cases associated with a Ph-like signature are enriched for activating JAK2 and CRLF2 mutations. These CRLF2 -r cases can be distinguished by increased expression of MUC4, GPR110 and IL2RA . Non-Ph-like CRLF2 -r leukemias may harbor alternate secondary lesions including RAS pathway mutations.